Abstract
The mouse mammary gland is widely used as a model for human breast cancer and has greatly added to our understanding of the molecular mechanisms involved in breast cancer development and progression. To fully appreciate the validity and limitations of the mouse model, it is essential to be aware of the similarities and also the differences that exist between the mouse mammary gland and the human breast. This introduction therefore describes the parallels and contrasts in mouse mammary gland and human breast morphogenesis from an early embryonic phase through to puberty, adulthood, pregnancy, parturition, and lactation, and finally the regressive stage of involution.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Propper A, Gomot L (1967) Tissue interactions during organogenesis of the mammary gland in the rabbit embryo. C R Acad Sci Hebd Seances Acad Sci D 264(22):2573–2575
Daniel CW, Smith GH (1999) The mammary gland: a model for development. J Mammary Gland Biol Neoplasia 4(1):3–8
Humphreys RC, Krajewska M, Krnacik S, Jaeger R, Weiher H, Krajewski S, Reed JC, Rosen JM (1996) Apoptosis in the terminal endbud of the murine mammary gland: a mechanism of ductal morphogenesis. Development 122(12):4013–4022
Hennighausen L, Robinson GW (1998) Think globally, act locally: the making of a mouse mammary gland. Genes Dev 12(4):449–455
Strange R, Li F, Saurer S, Burkhardt A, Friis RR (1992) Apoptotic cell death and tissue remodelling during mouse mammary gland involution. Development 115(1):49–58
Richert MM, Schwertfeger KL, Ryder JW, Anderson SM (2000) An atlas of mouse mammary gland development. J Mammary Gland Biol Neoplasia 5(2):227–241
Parmar H, Cunha GR (2004) Epithelial-stromal interactions in the mouse and human mammary gland in vivo. Endocr Relat Cancer 11(3):437–458
Hennighausen L, Robinson GW (2001) Signaling pathways in mammary gland development. Dev Cell 1(4):467–475
Russo IH, Russo J (1996) Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect 104(9):938–967
Bolander FF Jr (1990) Differential characteristics of the thoracic and abdominal mammary glands from mice. Exp Cell Res 189(1):142–144
Daniel CW, Silberstein GB, Strickland P (1987) Direct action of 17 beta-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography. Cancer Res 47(22):6052–6057
Sakakura T, Kusano I, Kusakabe M, Inaguma Y, Nishizuka Y (1987) Biology of mammary fat pad in fetal mouse: capacity to support development of various fetal epithelia in vivo. Development 100(3):421–430
Russo J, Russo IH (2004) Development of the human breast. Maturitas 49(1):2–15. doi:10.1016/j.maturitas.2004.04.011
Kratochwil K (1971) In vitro analysis of the hormonal basis for the sexual dimorphism in the embryonic development of the mouse mammary gland. J Embryol Exp Morphol 25(1):141–153
Howard BA, Gusterson BA (2000) Human breast development. J Mammary Gland Biol Neoplasia 5(2):119–137
Veltmaat JM, Mailleux AA, Thiery JP, Bellusci S (2003) Mouse embryonic mammogenesis as a model for the molecular regulation of pattern formation. Differentiation 71(1):1–17. doi:10.1046/j.1432-0436.2003.700601.x
Anbazhagan R, Osin PP, Bartkova J, Nathan B, Lane EB, Gusterson BA (1998) The development of epithelial phenotypes in the human fetal and infant breast. J Pathol 184(2):197–206. doi:10.1002/(SICI)1096-9896(199802)184:2<197::AID-PATH992>3.0.CO;2-J
Petersen OW, Polyak K (2010) Stem cells in the human breast. Cold Spring Harb Perspect Biol 2(5):a003160. doi:10.1101/cshperspect.a003160
Sun P, Yuan Y, Li A, Li B, Dai X (2010) Cytokeratin expression during mouse embryonic and early postnatal mammary gland development. Histochem Cell Biol 133(2):213–221. doi:10.1007/s00418-009-0662-5
Chu EY, Hens J, Andl T, Kairo A, Yamaguchi TP, Brisken C, Glick A, Wysolmerski JJ, Millar SE (2004) Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development 131(19):4819–4829. doi:10.1242/dev.01347
Eblaghie MC, Song SJ, Kim JY, Akita K, Tickle C, Jung HS (2004) Interactions between FGF and Wnt signals and Tbx3 gene expression in mammary gland initiation in mouse embryos. J Anat 205(1):1–13. doi:10.1111/j.0021-8782.2004.00309.x
Veltmaat JM, Van Veelen W, Thiery JP, Bellusci S (2004) Identification of the mammary line in mouse by Wnt10b expression. Dev Dyn 229(2):349–356. doi:10.1002/dvdy.10441
Mailleux AA, Spencer-Dene B, Dillon C, Ndiaye D, Savona-Baron C, Itoh N, Kato S, Dickson C, Thiery JP, Bellusci S (2002) Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Development 129(1):53–60
Foley J, Dann P, Hong J, Cosgrove J, Dreyer B, Rimm D, Dunbar M, Philbrick W, Wysolmerski J (2001) Parathyroid hormone-related protein maintains mammary epithelial fate and triggers nipple skin differentiation during embryonic breast development. Development 128(4):513–525
Hovey RC, Harris J, Hadsell DL, Lee AV, Ormandy CJ, Vonderhaar BK (2003) Local insulin-like growth factor-II mediates prolactin-induced mammary gland development. Mol Endocrinol 17(3):460–471. doi:10.1210/me.2002-0214
Asch HL, Asch BB (1985) Expression of keratins and other cytoskeletal proteins in mouse mammary epithelium during the normal developmental cycle and primary culture. Dev Biol 107(2):470–482
Radice GL, Ferreira-Cornwell MC, Robinson SD, Rayburn H, Chodosh LA, Takeichi M, Hynes RO (1997) Precocious mammary gland development in P-cadherin-deficient mice. J Cell Biol 139(4):1025–1032
Ingman WV, Robertson SA (2008) Mammary gland development in transforming growth factor beta1 null mutant mice: systemic and epithelial effects. Biol Reprod 79(4):711–717
Russo IH, Russo J (2011) Pregnancy-induced changes in breast cancer risk. J Mammary Gland Biol Neoplasia 16(3):221–233. doi:10.1007/s10911-011-9228-y
Brisken C, Duss S (2007) Stem cells and the stem cell niche in the breast: an integrated hormonal and developmental perspective. Stem Cell Rev 3(2):147–156
Sternlicht MD, Kouros-Mehr H, Lu P, Werb Z (2006) Hormonal and local control of mammary branching morphogenesis. Differentiation 74(7):365–381
Silberstein GB, Strickland P, Coleman S, Daniel CW (1990) Epithelium-dependent extracellular matrix synthesis in transforming growth factor-beta 1-growth-inhibited mouse mammary gland. J Cell Biol 110(6):2209–2219
McNally S, Martin F (2011) Molecular regulators of pubertal mammary gland development. Ann Med 43(3):212–234. doi:10.3109/07853890.2011.554425
Topper YJ, Freeman CS (1980) Multiple hormone interactions in the developmental biology of the mammary gland. Physiol Rev 60:1049–1056
Brisken C (2002) Hormonal control of alveolar development and its implications for breast carcinogenesis. J Mammary Gland Biol Neoplasia 7(1):39–48
Deroo BJ, Hewitt SC, Collins JB, Grissom SF, Hamilton KJ, Korach KS (2009) Profile of estrogen-responsive genes in an estrogen-specific mammary gland outgrowth model. Mol Reprod Dev 76(8):733–750
Couse JF, Korach KS (1999) Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 20(3):358–417
Bocchinfuso WP, Korach KS (1997) Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J Mammary Gland Biol Neoplasia 2(4):323–334
Mallepell S, Krust A, Chambon P, Brisken C (2006) Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci U S A 103(7):2196–2201
LaMarca HL, Rosen JM (2008) Minireview: hormones and mammary cell fate – what will I become when I grow up? Endocrinology 149(9):4317–4321
Britt K, Ashworth A, Smalley M (2007) Pregnancy and the risk of breast cancer. Endocr Relat Cancer 14(4):907–933. doi:10.1677/ERC-07-0137
Atwood CS, Hovey RC, Glover JP, Chepko G, Ginsburg E, Robison WG, Vonderhaar BK (2000) Progesterone induces side-branching of the ductal epithelium in the mammary glands of peripubertal mice. J Endocrinol 167(1):39–52
Silberstein GB (2001) Postnatal mammary gland morphogenesis. Microsc Res Tech 52(2):155–162. doi:10.1002/1097-0029(20010115)52:2<155::AID-JEMT1001>3.0.CO;2-P
Nelson CM, Vanduijn MM, Inman JL, Fletcher DA, Bissell MJ (2006) Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures. Science (New York, NY) 314(5797):298–300
Olijnyk D, Ibrahim AM, Ferrier RK, Tsuda T, Chu ML, Gusterson BA, Stein T, Morris JS (2014) Fibulin-2 is involved in early extracellular matrix development of the outgrowing mouse mammary epithelium. Cell Mol Life Sci 71(19):3811–3828. doi:10.1007/s00018-014-1577-4
Kamalati T, Niranjan B, Yant J, Buluwela L (1999) HGF/SF in mammary epithelial growth and morphogenesis: in vitro and in vivo models. J Mammary Gland Biol Neoplasia 4(1):69–77
Niranjan B, Buluwela L, Yant J, Perusinghe N, Atherton A, Phippard D, Dale T, Gusterson B, Kamalati T (1995) HGF/SF: a potent cytokine for mammary growth, morphogenesis and development. Development 121(9):2897–2908
Soriano JV, Pepper MS, Orci L, Montesano R (1998) Roles of hepatocyte growth factor/scatter factor and transforming growth factor-beta1 in mammary gland ductal morphogenesis. J Mammary Gland Biol Neoplasia 3(2):133–150
Pollard JW (2001) Tumour-stromal interactions. Transforming growth factor-beta isoforms and hepatocyte growth factor/scatter factor in mammary gland ductal morphogenesis. Breast Cancer Res 3(4):230–237
Andres AC, Strange R (1999) Apoptosis in the estrous and menstrual cycles. J Mammary Gland Biol Neoplasia 4(2):221–228
Russo J, Gusterson BA, Rogers AE, Russo IH, Wellings SR, van Zwieten MJ (1990) Comparative study of human and rat mammary tumorigenesis. Lab Invest 62(3):244–278
Visvader JE (2009) Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev 23(22):2563–2577. doi:10.1101/gad.1849509
Moll R, Franke WW, Schiller DL, Geiger B, Krepler R (1982) The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31(1):11–24
Nandi S (1958) Endocrine control of mammary-gland development and function in the C3H/He Crgl mouse. J Natl Cancer Inst 21(6):1039–1063
Neville MC, McFadden TB, Forsyth I (2002) Hormonal regulation of mammary differentiation and milk secretion. J Mammary Gland Biol Neoplasia 7(1):49–66
Traurig HH (1967) A radioautographic study of cell proliferation in the mammary gland of the pregnant mouse. Anat Rec 159(2):239–247. doi:10.1002/ar.1091590213
Brisken C, Park S, Vass T, Lydon JP, O'Malley BW, Weinberg RA (1998) A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc Natl Acad Sci U S A 95(9):5076–5081
Humphreys RC, Lydon J, O'Malley BW, Rosen JM (1997) Mammary gland development is mediated by both stromal and epithelial progesterone receptors. Mol Endocrinol 11(6):801–811. doi:10.1210/mend.11.6.9891
Conneely OM, Mulac-Jericevic B, Lydon JP (2003) Progesterone-dependent regulation of female reproductive activity by two distinct progesterone receptor isoforms. Steroids 68(10-13):771–778
Bradbury JM, Edwards PA, Niemeyer CC, Dale TC (1995) Wnt-4 expression induces a pregnancy-like growth pattern in reconstituted mammary glands in virgin mice. Dev Biol 170(2):553–563. doi:10.1006/dbio.1995.1236
Fernandez-Valdivia R, Mukherjee A, Ying Y, Li J, Paquet M, DeMayo FJ, Lydon JP (2009) The RANKL signaling axis is sufficient to elicit ductal side-branching and alveologenesis in the mammary gland of the virgin mouse. Dev Biol 328(1):127–139. doi:10.1016/j.ydbio.2009.01.019
Brisken C, Heineman A, Chavarria T, Elenbaas B, Tan J, Dey SK, McMahon JA, McMahon AP, Weinberg RA (2000) Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev 14(6):650–654
Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, Elliott R, Scully S, Voura EB, Lacey DL, Boyle WJ, Khokha R, Penninger JM (2000) The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103(1):41–50
Mulac-Jericevic B, Lydon JP, DeMayo FJ, Conneely OM (2003) Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci U S A 100(17):9744–9749. doi:10.1073/pnas.1732707100
Brisken C, Kaur S, Chavarria TE, Binart N, Sutherland RL, Weinberg RA, Kelly PA, Ormandy CJ (1999) Prolactin controls mammary gland development via direct and indirect mechanisms. Dev Biol 210(1):96–106. doi:10.1006/dbio.1999.9271
Ormandy CJ, Naylor M, Harris J, Robertson F, Horseman ND, Lindeman GJ, Visvader J, Kelly PA (2003) Investigation of the transcriptional changes underlying functional defects in the mammary glands of prolactin receptor knockout mice. Recent Prog Horm Res 58:297–323
Harris J, Stanford PM, Sutherland K, Oakes SR, Naylor MJ, Robertson FG, Blazek KD, Kazlauskas M, Hilton HN, Wittlin S, Alexander WS, Lindeman GJ, Visvader JE, Ormandy CJ (2006) Socs2 and elf5 mediate prolactin-induced mammary gland development. Mol Endocrinol 20(5):1177–1187. doi:10.1210/me.2005-0473
Adams JC, Watt FM (1993) Regulation of development and differentiation by the extracellular matrix. Development 117(4):1183–1198
Howlett AR, Bissell MJ (1993) The influence of tissue microenvironment (stroma and extracellular matrix) on the development and function of mammary epithelium. Epithelial Cell Biol 2(2):79–89
Fata JE, Werb Z, Bissell MJ (2004) Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast Cancer Res 6(1):1–11. doi:10.1186/bcr634
Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z (2006) GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 127(5):1041–1055. doi:10.1016/j.cell.2006.09.048
Nguyen DA, Parlow AF, Neville MC (2001) Hormonal regulation of tight junction closure in the mouse mammary epithelium during the transition from pregnancy to lactation. J Endocrinol 170(2):347–356
Russo J, Russo IH (1987) The mammary gland: development, regulation and function. Plenum, New York, NY
Lee S, Medina D, Tsimelzon A, Mohsin SK, Mao S, Wu Y, Allred DC (2007) Alterations of gene expression in the development of early hyperplastic precursors of breast cancer. Am J Pathol 171(1):252–262
LaMarca HL, Rosen JM (2007) Estrogen regulation of mammary gland development and breast cancer: amphiregulin takes center stage. Breast Cancer Res 9(4):304
Johnston SR (2006) Clinical efforts to combine endocrine agents with targeted therapies against epidermal growth factor receptor/human epidermal growth factor receptor 2 and mammalian target of rapamycin in breast cancer. Clin Cancer Res 12(3):1061–1068
Chen CC, Stairs DB, Boxer RB, Belka GK, Horseman ND, Alvarez JV, Chodosh LA (2012) Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways. Genes Dev 26(19):2154–2168. doi:10.1101/gad.197343.112
Wagner KU, Krempler A, Triplett AA, Qi Y, George NM, Zhu J, Rui H (2004) Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice. Mol Cell Biol 24(12):5510–5520. doi:10.1128/MCB.24.12.5510-5520.2004
Brisken C, Ayyannan A, Nguyen C, Heineman A, Reinhardt F, Tan J, Dey SK, Dotto GP, Weinberg RA (2002) IGF-2 is a mediator of prolactin-induced morphogenesis in the breast. Dev Cell 3(6):877–887
Prilusky J, Deis RP (1975) Effect of L-dopa on milk ejection and prolactin release in lactating rats. J Endocrinol 67(3):397–401
Mather IH, Keenan TW (1998) Origin and secretion of milk lipids. J Mammary Gland Biol Neoplasia 3(3):259–273
Neville MC (1999) Physiology of lactation. Clin Perinatol 26(2):251–279, v
Abell K, Bilancio A, Clarkson RW, Tiffen PG, Altaparmakov AI, Burdon TG, Asano T, Vanhaesebroeck B, Watson CJ (2005) Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition. Nat Cell Biol 7(4):392–398. doi:10.1038/ncb1242
Schwertfeger KL, Richert MM, Anderson SM (2001) Mammary gland involution is delayed by activated Akt in transgenic mice. Mol Endocrinol 15(6):867–881. doi:10.1210/mend.15.6.0663
Li M, Liu X, Robinson G, Bar-Peled U, Wagner KU, Young WS, Hennighausen L, Furth PA (1997) Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution. Proc Natl Acad Sci U S A 94(7):3425–3430
Feng Z, Marti A, Jehn B, Altermatt HJ, Chicaiza G, Jaggi R (1995) Glucocorticoid and progesterone inhibit involution and programmed cell death in the mouse mammary gland. J Cell Biol 131(4):1095–1103
Kreuzaler PA, Staniszewska AD, Li W, Omidvar N, Kedjouar B, Turkson J, Poli V, Flavell RA, Clarkson RW, Watson CJ (2011) Stat3 controls lysosomal-mediated cell death in vivo. Nat Cell Biol 13(3):303–309. doi:10.1038/ncb2171
Monks J, Rosner D, Geske FJ, Lehman L, Hanson L, Neville MC, Fadok VA (2005) Epithelial cells as phagocytes: apoptotic epithelial cells are engulfed by mammary alveolar epithelial cells and repress inflammatory mediator release. Cell Death Differ 12(2):107–114. doi:10.1038/sj.cdd.4401517
Monks J, Smith-Steinhart C, Kruk ER, Fadok VA, Henson PM (2008) Epithelial cells remove apoptotic epithelial cells during post-lactation involution of the mouse mammary gland. Biol Reprod 78(4):586–594. doi:10.1095/biolreprod.107.065045
Clarkson RW, Wayland MT, Lee J, Freeman T, Watson CJ (2004) Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression. Breast Cancer Res 6(2):R92–R109. doi:10.1186/bcr754
Marti A, Jehn B, Costello E, Keon N, Ke G, Martin F, Jaggi R (1994) Protein kinase A and AP-1 (c-Fos/JunD) are induced during apoptosis of mouse mammary epithelial cells. Oncogene 9(4):1213–1223
Marti A, Lazar H, Ritter P, Jaggi R (1999) Transcription factor activities and gene expression during mouse mammary gland involution. J Mammary Gland Biol Neoplasia 4(2):145–152
Stein T, Morris JS, Davies CR, Weber-Hall SJ, Duffy MA, Heath VJ, Bell AK, Ferrier RK, Sandilands GP, Gusterson BA (2004) Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res 6(2):R75–R91. doi:10.1186/bcr753
Lund LR, Romer J, Thomasset N, Solberg H, Pyke C, Bissell MJ, Dano K, Werb Z (1996) Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways. Development 122(1):181–193
Watson CJ, Kreuzaler PA (2011) Remodeling mechanisms of the mammary gland during involution. Int J Dev Biol 55(7-9):757–762. doi:10.1387/ijdb.113414cw
O'Brien J, Martinson H, Durand-Rougely C, Schedin P (2012) Macrophages are crucial for epithelial cell death and adipocyte repopulation during mammary gland involution. Development 139(2):269–275. doi:10.1242/dev.071696
Balogh GA, Heulings R, Mailo DA, Russo PA, Sheriff F, Russo IH, Moral R, Russo J (2006) Genomic signature induced by pregnancy in the human breast. Int J Oncol 28(2):399–410
Hutson SW, Cowen PN, Bird CC (1985) Morphometric studies of age related changes in normal human breast and their significance for evolution of mammary cancer. J Clin Pathol 38(3):281–287
Milanese TR, Hartmann LC, Sellers TA, Frost MH, Vierkant RA, Maloney SD, Pankratz VS, Degnim AC, Vachon CM, Reynolds CA, Thompson RA, Melton LJ 3rd, Goode EL, Visscher DW (2006) Age-related lobular involution and risk of breast cancer. J Natl Cancer Inst 98(22):1600–1607. doi:10.1093/jnci/djj439
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Science+Business Media New York
About this protocol
Cite this protocol
McNally, S., Stein, T. (2017). Overview of Mammary Gland Development: A Comparison of Mouse and Human. In: Martin, F., Stein, T., Howlin, J. (eds) Mammary Gland Development. Methods in Molecular Biology, vol 1501. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6475-8_1
Download citation
DOI: https://doi.org/10.1007/978-1-4939-6475-8_1
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-6473-4
Online ISBN: 978-1-4939-6475-8
eBook Packages: Springer Protocols